A Graphene Nanoparticle-Based X-ray Computed Tomography Contrast Agent ForSubjects At Risk for Contrast Induced Nephropathy

摘要 这项SBIR第一阶段的提案旨在证明一种新型的临床前安全性和有效性 基于碳纳米结构的X射线CT成像造影剂(CA) 以及对肾功能衰竭或有造影剂肾病(CIN)风险的患者进行监测。 常规增强CT扫描传递有关疾病和损伤的关键信息， 从而帮助临床医生改进对患者的诊断和管理。当今世界 市场上可用的CT-CA都是基于共价键合的三碘苯环。 然而，它们都是肾功能不全、糖尿病、心力衰竭患者的禁忌。 和甲状腺功能障碍。在这些患者队列中使用这些CT CA与CIN有关 这会恶化正常或进一步加剧原有的肾功能。这些不利因素 影响与高渗透压和高粘度的CT血管造影和不能 这些甚至是低或等渗和/或等粘的CT CA配方要完全 消除溶液中细胞毒性的游离碘离子。 这项提案中详细介绍的技术建立在我们之前报告的新型碳- 基于纳米颗粒的T1等渗、等粘磁共振成像(MRI)CA。这 由锰(Mn2+)共价插入氧化石墨烯纳米小片(GNP)组成 用右旋糖苷官能化，命名为GNP-Dex。该配方急性毒性低， 血液稳定性高，通过尿液对肾脏的清除量高。对于扩展的多式联运使用， 我们将碘离子插层并共价官能化到石墨烯内层。 这种隔离碘的方法防止了它以自由离子的形式解离到溶液中。这 我们称之为GNP-I的配方。肾上皮细胞培养的体外研究 表现出良好的GNP-I细胞相容性。此外，在等摩尔浓度下， 碘、GNP-I在模体中显示非常高的CT(~10倍)放射不透明信号 与对照-碘海醇(Omnipaque™)--一种常用的CT CA相比。因此这些较低的 检测极限将允许在相当低的剂量下具有相同的临床成像性能， 从而降低医疗成本。 基于GNP-I的特征，包括其明显高于 对于现有的CT CA，本提案的主旨是专门为 对CIN高危患者的肾脏和其他重要器官的监测和诊断。因此， 从而克服了目前CT CA的局限性。为此，我们将进行临床前 在一个经过良好验证的急性肾损伤啮齿动物模型中进行安全性和有效性可行性研究 就是5/6的Nephrex老鼠。成功完成本提案中概述的目标将导致 提交SBIR第二阶段提案，在临床前进行安全性和有效性研究 在良好的实验室操作规范(GLP)下建立合适的大型动物模型，然后进行调查 向FDA提交新药(IND)申请。此外，成功的发展将导致 第一个FDA批准的CT CA专门用于这些明显处于不利地位的高风险 病人组。

Abstract This SBIR phase 1 proposal is to demonstrate the pre-clinical safety and efficacy of a novel carbon-nanostructure-based X-ray computer tomography (CT) contrast agent (CA) for imaging and monitoring in patients with renal failure or at risk of contrast induced nephropathy (CIN). Routine contrast enhanced CT scans relays crucial information about diseases and injuries, thus aiding the clinician in improving diagnosis and management of patients. The present day CT CAs available on the market are all based on covalently bonded tri-iodinated benzene rings. However, they are all contraindicated for patients with renal insufficiency, diabetes, heart failure and thyroid dysfunction. Use of these CT CAs in these patient cohorts has been linked to CIN which deteriorates normal or further exacerbate pre-existing kidney functions. These adverse effects have been associated with high osmolality and viscosity CT CAs and the inability of these and even low or iso-osmolar and/or iso-viscous CT CA formulations to be completely eliminated of cytotoxic free iodine ions in solution. The technology detailed in this proposal builds on our previously reported novel carbon- nanoparticle based T1 iso-osmolar, iso-viscous Magnetic Resonance Imaging (MRI) CA. This comprises of manganese (Mn2+) intercalated graphene oxide nanoplatelets (GNP) covalently functionalized with dextran, and named GNP-Dex. This formulation shows low acute toxicity, high blood stability and high renal clearance through the urine. For expanded multimodal use, we intercalated and covalently functionalized iodine ions to the inner graphene sheet layers. This method of sequestration of iodine prevents its dissociation as free ions into solution. This formulation we termed GNP-I. In vitro studies done on kidney epithelial cell culture demonstrated favorable GNP-I cyto-compatibility. Furthermore, at equimolar concentration of iodine, GNP-I showed very high CT (~10 times greater) radio-opacity signals in phantoms compared to the control–Iohexol (Omnipaque™) – a commonly used CT CA. Thus these lower detection limits will allow the same clinical imaging performance at substantially lower dosages, thus lowering healthcare costs. Based on GNP-I characteristics, inclusive of its apparent higher safety and efficacy profiles than that of currently available CT CAs, the thrust in this proposal is to develop it specifically for monitoring and diagnosis of kidney and other vital organs for patients at risk of CIN. Thus, thereby overcoming the limitations of present day CT CAs. For this, we will conduct pre-clinical safety and efficacy feasibility studies in a well validated rodent model of acute kidney injury, that is, the 5/6 Nephrex rat. Successful completion of the aims outlined in this proposal will lead to submission of a SBIR phase 2 proposal to perform safety and efficacy pre-clinical studies in a suitable large animal model under good laboratory practice (GLP) followed by Investigational New Drug (IND) application to the FDA. Furthermore, successful development will lead to the first FDA- approved CT CA specifically for use in these high risks, distinctly disadvantaged patient groups.